Devices for integrated indirect sweat stimulation and sensing

ABSTRACT

A sweat sensing device (20) comprises at least one sweat generation unit (22) capable of initiating sudomotor axon reflex (SAR) sweating in an indirect stimulation region and at least one analysis unit (24, 26) capable of sensing a physiological parameter of sweat, collecting a sweat sample, or a combination thereof. The at least one analysis unit (24, 26) is located above the indirect stimulation region when the sweat sensing device is placed on skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of the filing dateof U.S. Patent Application Publication No. 2018/0035928 A1 (U.S. patentapplication Ser. No. 15/544,725), filed on Jul. 19, 2017, which is theU.S. national phase of International Patent Application No.PCT/US2016/017726 (International Patent Application Publication No. WO2016/130905 A1), filed on Feb. 12, 2016, which claims benefit of U.S.Patent Application No. 62/115,851, filed on Feb. 13, 2015, thedisclosures of which are hereby incorporated by reference herein intheir entireties.

BACKGROUND OF THE INVENTION

Historically, partitioning of biomarkers from blood to sweat has beendemonstrated in great detail. As more of these biomarkers emerge, sweatappears to be a convincing media for continuous and spontaneous healthmonitoring. However, ‘clinical’ techniques of sample collection,purification and analysis have restricted growth in the sweat-sensingarea because of the cost and time associated with these techniques. Withthe advent of miniaturized sensors, however, many of these issues can bealleviated. Still, a large task has largely been left unexplored forcompact sweat sensing technologies: sample extraction and collection.

Common techniques for sweat stimulation and analysis involve sweatstimulation in a region from a sweat generating unit 10, followed byremoval of this unit 10 from the skin 12, cleaning of the skin 12 andreapplication of a sensing unit 14 or collection device 16, as shown inFIGS. 1A-1C. Often, the sensing unit 14 has integrated communicationprotocol to alert the user. This communication method could be viawireless or wired connections. For example, cystic fibrosis testingoften involves this technique as demonstrated by ELITechGroup® in theirMacroduct® and Nanoduct® products. This technique is problematic becauseit requires a two-step process that is inconvenient, non-continuous, andwhere reproducibility could be difficult.

Further, contamination from the stimulation reservoir and sensor regionis unavoidable as they share the same area. In reference to FIGS. 1A-1C,the sweat generation unit 10 has potential to alter the state of theskin 12, whether that includes excessive hydration, thermal heating,irritation, pharmacological side-effects, or another side effect. Thisadds a confounding factor to sensing sweat analytes when the sensingunit 14 or collection device 16 is placed on the skin.

Attempts to reduce contamination have previously been made. For example,a technique includes utilizing an isolating membrane between sweatstimulation mechanisms and the sensors and sensing sites. However, suchtechniques utilizing isolating membranes (or similar techniques) mayonly partially or temporarily separate sweat stimulation mechanisms,such as an electric field and/or chemicals, from the sensors and sensingsites. In the instance of isolating membranes, these also have thedrawback of increasing the dead volume between a sensor and the skin 12,which reduces temporal resolution. Furthermore, horizontal iontophoreticdriving of an iontophoretic chemical, such as pilocarpine, may be used.However, this will again subject the sensor, sweat, and skin to anelectric field and/or contamination. For many biomarkers and sensors,such interference could reduce performance of a sweat sensing device, insome cases making sensing impossible. There is an increasing need toprovide improved sweat sensing techniques and devices that address oneor more of the above drawbacks.

SUMMARY OF THE INVENTION

Embodiments of the present invention rely in part on the premise thatsudomotor axon reflex (SAR) sweating can be utilized by a sweat inducingand sensing device for sweat analysis. SAR sweating can potentially beinitiated by a variety of mechanisms: thermal, direct-electrical,chemical, occlusion, and others. In this setting, direct-electricalrefers to a biophysical phenomenon where sweating is initiated by theflow of electron and ion current without the aid of a chemical activecompound. Additionally, embodiments of the present invention can greatlyreduce contamination and improve chronological sampling of sweat.Furthermore, the embodiments of the present invention described belowhave the ability to use a variety of sensing techniques which greatlyimproves the impact and variety of applications for such a device.

BRIEF DESCRIPTION OF THE DRAWINGS

The objects and advantages of the present invention will be furtherappreciated in light of the following detailed descriptions and drawingsin which:

FIGS. 1A-IC are cross-sectional views of a prior art sweat stimulation,sensing, and collection technique;

FIG. 2 is a cross-sectional view of a device according to an embodimentof the present invention showing separate sensing and collection units;

FIG. 3 is a cross-sectional view of a device according to anotherembodiment of the present invention showing the sensing and collectionunits embedded within the sweat generation unit;

FIG. 4A is a top view of a device according to another embodiment of thepresent invention showing a hexagonal arrangement;

FIG. 4B is a cross-sectional view of the device of FIG. 4A;

FIG. 5 is a top view of a device according to another embodiment of thepresent invention showing a high aspect ratio arrangement;

FIGS. 6A and 6B are cross-sectional views of devices according toembodiments of the present invention showing a fluid management systemin differing arrangements; and

FIGS. 6C and 6D are perspective views of devices according toembodiments of the present invention showing a fluid management systemin differing arrangements.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described herein improvegreatly on prior simultaneous stimulation and collection of sweat samplemethods, such as that presented in FIG. 1.

Embodiments of the present invention take advantage of a biologicalresponse referred to as the sudomotor axon reflex (“SAR”). Thismechanism acts on the premise that innervation of sweat glands occurs asa result of peripheral functionality of sudomotor units (i.e., the bodywill stimulate a series of sweat glands directly underneath thestimulation region, “direct stimulation”, but will also generate sweatfrom sweat glands outside of this region, “indirect stimulation”). Forexample, in the case of chemical sweat stimulation, the sweat stimulantacts on the neural receptors surrounding the sweat glands to elicit asweating response. The chemical stimulant can act on two primaryreceptors at the base of the sweat gland: muscarinic or nicotinicreceptors. SAR response is typically observed with chemicals thatinteract strongly with nicotinic receptors at the base of the sweatgland. For example, pilocarpine acts weakly on nicotinic receptors andis therefore a poor chemical stimulant for SAR response. However,nicotine acts strongly on nicotinic receptors and is therefore anattractive stimulant for SAR response. Furthermore, there are chemicalstimulants, such as acetylcholine, that act strongly on both muscarinicand nicotinic receptors, which can be leveraged to produce a SARresponse. It should be recognized that, although not named, multipleother chemical stimulants are capable of causing a SAR response and areuseful in embodiments of the present invention. Although there haslargely been limited research in this area of sweat stimulation, it isalso hypothesized that thermal, direct-electrical, occlusion, and othersweat stimulant techniques will produce a similar antidromic responsesas chemical stimulants. Consequently, one can stimulate sweat glands ina region within close proximity of a sensor array to generate sweatdirectly underneath the stimulation region (“direct stimulation”) anddirectly underneath the sensors (“indirect stimulation”). Typically, the“spreading” of SAR induced sweating, the distance from the edge ofdirect stimulation to the decay of indirect stimulation, is limited onthe order of several tens of millimeters (e.g., up to about 30 mm). Thedegree of a SAR response, in the case of chemical stimulation, dependslargely on the amount and type of sweat stimulant which is delivered toa given location.

In reference to FIG. 2, a device 20 according to an embodiment of thepresent invention may have a structure with a sweat generation unit 22and at least one of two analysis units: a collection unit 24 and asensing unit 26. The sweat generation unit 22 is capable of directlyinitiating sweat in a direct stimulation region and initiating SARsweating in indirect stimulation regions under the collection unit 24and the sensing unit 26. In one embodiment, the sweat generation unit 22includes a chemical stimulant, such as acetylcholine, methacholine,nicotine, carbachol, or another chemical that is capable of initiatingSAR sweat. The collection unit 24 and the sensing unit 26 are locatedseparately from the sweat generation unit 22 along the skin 12. In oneembodiment, the analysis units may be spaced apart from the directstimulation region by a distance of about 0.1 mm to about 30 mm. TheSAR-initiated sweat is then collected and sensed by the collection unit24 and the sensing unit 26, respectively. As shown, embodiments of thepresent invention promote a single-step process, which is an advantageover previous devices where sweat generation and sweat analysis wereperformed in multiple steps. Further, continuous and multiple occurrenceSAR-initiated sweating for the purpose of sweat analysis is possible.For example, sweat may be sensed or collected in one instance in time,continuously for a length of time, or a combination thereof.

Optionally, each of these regions (sweat generation, sweat sensing, andsweat collecting) may be separated by an isolation layer 28 as shown inFIG. 2. This isolation layer 28 could take many forms or materials suchas an adhesive or rubber with the purpose of electrically and/orfluidically isolating regions of the device. The isolation layer 28serves to improve the reliability of the device and helps assure thatfluid will not mix between regions or create unwanted electricalconnections (e.g., “electrical shorts”). Furthermore, since thisisolation layer 28 is preferably water-insoluble, common adhesives willnot only provide electric and fluidic isolation but will also aid inkeeping the device on the skin 12. Furthermore, in some cases, theisolation layer 28 protects the sensing unit 26 from voltages orcurrents applied to the sweat generation unit 22.

The term “sweat generation unit”, including other denotative orconnotative phrases, as used herein, captures a plurality of sweatstimulation methods that are capable of initiating SAR sweating. Forexample, a sweat generation unit may involve one or more of chemical,thermal, direct-electrical, or other suitable mechanisms whichstimulates the generation of sweat and are not specifically described.The most common technique for sweat stimulation is a chemical techniquereferred to as iontophoresis. This involves electric-field drivenmovement of a sweat stimulant drug into the skin surface, ultimatelyreaching the secretory coil of the sweat gland, to initiate sweating. Itshould be recognized that, although iontophoresis is the most commonchemical technique, electroporation, injection or microneedles delivery,passive diffusion of a sweat stimulant from a drug reservoir, which maybe improved by a diffusion enhancer (e.g., propylene glycol) applied tothe skin prior to device application or incorporated directly into thestimulation unit itself, or other techniques are also possible routes ofchemical delivery of a sweat stimulant in embodiments of the presentinvention. Utilizing such a design according to the present inventionwill greatly reduce contamination between a stimulation reservoir (e.g.,in the sweat generation unit 22) and collection and/or the sensor region(e.g., relating to the collection unit 24 and the sensing unit 26).

Additionally, the terms “sensing unit” and “sensing mechanism,”including other denotative or connotative phrases, as used herein couldinclude one or more of a plurality of mechanisms for sensing sweatand/or its components or properties including potentiometric,amperometric, conductometric, impedance spectroscopy, skin impedance,galvanic skin response (GSR), or other suitable mechanisms. Similarly,the term “collection unit”, including other denotative or connotativephrases, as used herein, describes a collection method, material, orstructure.

The terms “collection and/or sensing unit” and “analysis unit”,including other denotative or connotative phrases, as used herein,describe a unit that is capable of sensing sweat, collecting sweat, or acombination of the two. A sensing unit (e.g., sensing unit 26) and/or acollection unit (e.g., collection unit 24) may have integratedelectronics or controls which monitor physiological parameters, providefeedback to a user or similar function. In an embodiment with both asensing unit(s) and a collection unit(s) (e.g., device 20), the unitsmay function independently of each other or may operate together.

Sweat generation units, collection units, sensing units, andcombinations of such units may include a variety of functional aspectssuch as wired or wireless communications, rigid or flexible structure orother method, material, function, or particular structure notspecifically described here. These units may also have intelligentcommunication between or within each unit via optical, electrical, orsimilar communication method (not shown).

In another embodiment, FIG. 3 shows a device 30 where a sweat generationunit 32 is placed in vertical alignment with a collection unit 34 and asensing unit 36. Although the collection 34 and/or sensing unit 36 areshown being located within the sweat generation unit 32, anotherembodiment may include at least one collection 34 and/or sensing unit 36located directly on skin 12 with the sweat generation unit 32 placeddirectly over said components (not shown). Although a minimal amount ofdirect sweating may possibly be produced underneath the collection unit34 or sensing unit 36 from the sweat generation unit 32, indirect (SAR)sweating may be the only suitable mechanism for generating sufficientsweat to sense and/or collect. For example, in the case of chemicalstimulation via iontophoresis, the collection unit 34 and the sensingunit 36 reduce the effectiveness for direct stimulation directlyunderneath these units. Essentially, these units block or alter theeffectiveness of a stimulation technique that initiates non-SARsweating. However, in leveraging SAR stimulation, the device 30 willovercome these limitations by indirectly generating sweat underneath theunits 34, 36. In other words, to generate sufficient sweat under thecollection unit 34 and the sensing unit 36, the sweat generation unit 32includes a mechanism for initiating SAR sweating.

The construction of device 30 could simplify device construction andassembly compared to other configurations. For example, in oneembodiment, units 34, 36 could be fabricated using standard flexibleelectronics techniques (such as on PET or Kapton film), and pressedagainst skin 12. The sweat generation unit 32 could be a gel including asweat stimulant and a driving electrode (not shown) that is pressed downagainst units 34, 36 and skin 12. Some of the iontophoretic chemicalstimulant in sweat generation unit 32 may find itself between units 34and 36 and skin (similar to as diagramed in FIG. 3), but would beincapable of generating a strong direct stimulation of sweat, and thusthis example embodiment would rely on the indirect stimulation of sweatby SAR to cause sweat to be received by units 34, 36.

A benefit of the vertical alignment between the analysis units (e.g.collection unit 34 and sensing unit 36) and a sweat generation unit(e.g., sweat generation unit 32) is an increase in the density of theunits. This benefit could be realized in other configurations of thesweat generation and analysis units, such as in the honeycomb formationdescribed below. Depending on the sweat generation mechanism,SAR-initiated sweat may only be able to be collected or sensed up toseveral millimeters away from the direct stimulation region. Therefore,embodiments of the present invention achieve a greater benefit with ahigh density of sweat generation and analysis units.

Regarding FIGS. 4A and 4B, in one embodiment, a device 40 is shownpositioned on the skin 12. The device 40 includes a plurality of sweatgeneration units 42 and a plurality of collection and/or sensing units44 arranged in a honeycomb structure. In one embodiment, the sweatgeneration units 42 are iontophoretic in nature and the collectionand/or sensing units 44 include potentiometric sensors. In thisconfiguration, the collection and/or sensing units 44 are placedspatially so that each unit 44 is within close proximity of a sweatgeneration unit 42 (i.e., the units 44 are located above indirectstimulation regions). With the hexagonal arrangement of device 40, eachsensing unit 44 is surrounded by three sweat generation units 42,increasing the probability for a SAR sweating response underneath thesensing units 44. The device 40 further includes an optional isolationmaterial 46 (best shown in FIG. 4B) that isolates the collection and/orsensing units 44 from the sweat generation units 42, which improves thedevice integrity and functionality. This isolation material 46 couldtake one of many forms and materials as previously described. Those ofordinary skill in the art will recognize that the structure may beconfigured to be a similar shape other than a hexagonal or a honeycombstructure. As shown in FIG. 4A, the stimulation source (i.e., the sweatgeneration units 42) and the collection and/or sensing units 44 areseparate in horizontal location on skin, with no horizontal overlap. Thepresent invention also contemplates devices where at least partialoverlap exists where the benefit of SAR sweating in the presentinvention is still realized, such as device 30 presented in FIG. 3.

Furthermore, in a device according to the present invention where thesweat generation method is via direct-electrical methods oriontophoresis, a return electrode can be placed on the periphery of thedevice so as to maximize the amount of current or drug delivered in thedesired location. For example, in FIG. 4A, a return electrode 48 ispositioned around an edge of the device 40.

In FIG. 5, a portion of a device 50 according to an embodiment of thepresent invention is shown. The device 50 includes a single large areaor a plurality of sweat generation units 52, a plurality of collectionand/or sensing units 54, and an optional isolation material 56. Thestructure utilizes a greater than unity aspect ratio of sensors and/orcollection units 54, which minimizes the amount of lateral distancerequired to leverage SAR sweating. Due to the need to be above at leastone active sweat gland, and/or due to signal to noise requirements, somecollection and or sensing units must have a minimum total area ofcontact with skin. A greater than unity aspect ratio allows a minimumarea to be achieved, while further minimizing the amount of lateraldistance required to leverage SAR sweating. In one embodiment, thelength/width aspect ratio may be about 2:1 or, alternatively, about 1:2.Although FIG. 5 shows a rectangular configuration, those of ordinaryskill in the art will recognize that a rectangular configuration is notrequired and a similarly intended effect can be achieved via aconcentric design or similar structure (not shown). For example, othergeometries, such as a star shape, may also be included that feature agreater than unity aspect ratio. Where the sweat generation method forthe device 50 is via direct-electrical methods or iontophoresis, areturn electrode 58 can be placed on the periphery of the device 50 soas to maximize the amount of current or drug delivered in the desiredlocation.

With reference to FIGS. 6A-6D, devices according to various embodimentsare shown that include improved sweat fluid management. Moreparticularly, devices 60 a, 60 b, 60 c, and 60 d are shown includingsweat generation unit(s) 62, collection and/or sensing unit(s) 64, andisolation materials 66. An optional wicking material 68 is used as anadditional component that acts as a fluid management feature, whichimproves performance. The wicking material 68 may also be used to bringsweat from skin 12 to a collection and/or sensing unit 64, as describedbelow. A device including the wicking material 68 may have varyingconfigurations. In one embodiment, the wicking material 68 may act toactively move previously analyzed sweat sample to a disposal region (notshown) thereby increasing effective sweat sampling time resolution. Forexample, the wicking material 68 may be included as a through-holecomponent in the collection and/or sensing unit 64 (FIG. 6A), at theedge of the collection and/or sensing unit 64 (FIG. 6B), or in the planeof the collection and/or sensing unit 64 (FIG. 6C). Further, thiswicking material 68 or similar microfluidic structure could be used totransport sweat from the skin to the collection and/or sensing unit(s)64 (specifically shown in FIG. 6D). For ease of fabrication or intendedapplication, one particular structure may be more beneficial thananother. For instance, regarding device 60 a, there may be benefit inwicking sweat to a central location within the collection and/or sensingunit 64 to reduce likelihood of fluid buildup near the isolationboundary 66. Similarly, in device 60 c, the wicking material 68 is shownpartially extended along the length of the sensor and/or collection unit64, which may prove beneficial where a small volume of sweat isgenerated underneath the sensor and/or collection unit 64 before beingwicked away. In this instance, the wicking material 68 acts as a static,volume-limiting pump. Furthermore, a combination of one of thestructures described may prove beneficial. In an exemplary embodiment,the wicking material 68 may be paper or a polymer or microfluidicfeature that operates via capillary action. Further, the wickingmaterial 68 could be segmented utilizing more than one wicking material,such as a combination of paper and polymer or another combination ofsimilar wicking materials.

Prediction of Typical Parameters

Peripheral (indirect) sweating after 5 minutes of iontophoresis issignificant (e.g., sweat rates of about 1-3 nL/min/gl) on average to atleast 8 mm from the boundary of the direct stimulation region. A sweatstimulant could be delivered iontophoretically or by another method andcould constitute a wide range of various sweat stimulants (e.g.,pilocarpine, acetylcholine, etc.). Considering that sensors can befabricated utilizing previously demonstrated technology well below 8 mmin diameter (e.g., 500 μm in diameter), an array of biomarker sensorsmay be easily placed within the indirect sweating region. Althoughindirect sweating results in a reduction in sweat rate (e.g., about 60%reduction as compared to the sweat rate in the area being directlystimulated), the reduction of the risk of contamination and potential toreduce drug dosage (as described below) outweigh this downfall.

The spacing between the stimulation regions and the collection and/orsensor units may vary depending on the configuration. In one embodiment,an array of stimulation units and analysis units may have a minimumhalf-pitch (smallest repeating unit) less than one millimeter at anaccuracy within tens of micrometers or better.

Sweat Stimulation—Sampling Effectiveness

A sampling effectiveness metric (“SE”) for comparing sweat stimulationdevices can be defined by Equation 1:

${SE} = \frac{Q}{\Gamma}$

where Q is the sweat rate per minute, and F is the dose of drugstimulant delivered in the case of iontophoretic delivery. A basemetric, e.g., SE₀, for the case of the stimulation region being the sameas the collection region (e.g., as shown in FIGS. 1A-IC) may be used tocompare sweat stimulation devices without using actual sweat rate data.The hexagonal device 40 shown in FIGS. 4A and 4B have one stimulationunit 42 per four total stimulation and collection/sensor units 42, 44per unit cell and would utilize at least ¼, or 25%, of the stimulationregion and, thus, 25% of the dosage Γ₀. Similarly, thesensing/collection regions would comprise 75% of the original area, A₀.Further, as described above, the hexagonal device 40 would generate 40%of the original sweat rate, Q₀, in the indirect regions. Therefore, incomparison to the case of the same stimulation and collection region, ahexagonal array would provide a decrease in total sweat rate of 70%(i.e., 100%−(40% Q₀*75% A₀)=70%), resulting in a sweat rate of 30% ofthe original sweat rate, Q₀, while using 25% of the original dose, Γ₀.This calculation completely excludes any sweat generated underneath thestimulation region. Overall however, the SE ratio would increase 20% asa result of the reduced stimulation area (i.e., 0.30 Q₀/0.25 Γ₀=1.2SE₀). Further, if one is able to collect the sweat generated underneaththe stimulation region, the SE could increase 120% (i.e., (0.30 Q₀+0.25Q₀)/0.25 Γ₀=2.2 SE₀). Thus, not only is the contamination reduced withthis method, but the sampling efficiency (SE) is increased. It should benoted that this reduction in area and ‘dose’ applies to all methods ofstimulation where these nerve fibers are activated. Therefore, thermal,direct-electrical or other methods would also benefit from this uniquedevice structure.

In alternative embodiments, the stimulation region could be much smallerthan the collection/sensor region. This is because only a small areawould be required to initiate the SAR response of many nearby sweatglands. Furthermore, in the case of iontophoresis, this reduction in thestimulation area would improve the SE, which would allow for less drugdelivery (dosage) to achieve the same previously attained SE.

Dead Volume

A metric for comparing the dead volume (“DV”) of such devices can bedefined by Equation 2:

${DV} = \frac{V_{dead}}{A_{sensor}}$

where V_(dead) is the dead volume between the sensor and skin, andA_(sensor) is the area of the sensor. Comparing to an instance where thestimulation and collection regions are in the same area and the deviceincludes an element to reduce contamination (not shown), such as amembrane, the gap between the sensor and skin could be on the order of200 μm (e.g., due to roughness of skin, thickness of paper wickinglayer, thickness of a drug reservoir, etc.). However, with indirectstimulation, one can greatly improve the contact between the skin andsensor while reducing the contamination from the stimulation. In thisregard, the device may be so intimate with the skin that the only sourceof dead volume would be from the topology of the skin (e.g., about 30μm). Thus, the reduction in dead volume between the device where thestimulation and collection regions are in the same area and thisembodiment would be a reduction of at least 6× (200 μm/30 μm). Thisholds great significance when one estimates the time to “refresh” thesweat underneath the sensor. If there is 6× less volume to refillunderneath the sensor, then for a given flow rate, the time required torefresh the sweat underneath the sensor would also be reduced 6×. Thishas profound impact on time-resolution capabilities.

Total Figure of Merit (TOT-FOM)

Utilizing the two calculations above for SE and DV and assuming theaddition of an isolating membrane between sensor and skin, the effectiveimprovement may be the multiplication of these two values. Therefore,the total improvement between an exemplary previous device describedabove and an embodiment of the present invention would be an improvementof at least 7.2× with potentially an improvement approaching 13.2×—whensweat rate per unit area, dose per unit area and dead volume per unitarea are considered.

While all of the invention has been illustrated by a description ofvarious embodiments and while these embodiments have been described inconsiderable detail, it is not the intention of the Applicants torestrict or in any way limit the scope of the appended claims to suchdetail. Additional advantages and modifications will readily appear tothose skilled in the art. The invention in its broader aspects istherefore not limited to the specific details, representative apparatusand method, and illustrative examples shown and described. Accordingly,departures may be made from such details without departing from thespirit or scope of the Applicants' general inventive concept.

What is claimed is:
 1. A wearable sweat sensing device, comprising: asweat stimulator configured to be placed on a surface of a first regionof a device wearer's skin to stimulate sweating in the first region andto stimulate sudomotor axon reflex (SAR) sweating in a second region ofthe wearer's skin, wherein the second region is distinct from the firstregion; and a sweat analyzer configured to be placed on a surface of thesecond region of the device wearer's skin, the sweat analyzer configuredto collect a sweat sample from the second region, and to measure one ormore analytes in the sweat sample.
 2. The device of claim 1, wherein thesweat stimulator is configured to have a minimum area in contact withthe device wearer's skin, a first dimension, and a second dimension, andwherein the ratio of the first dimension to the second dimension is oneor more of the following: greater than 1 to 1, 2 to 1, or greater than 2to
 1. 3. The device of claim 1, wherein the sweat stimulator isconfigured to have a surface area in contact with the device wearer'sskin, and a minimum volume relative to the surface area.
 4. The deviceof claim 1, further comprising one or more sweat stimulators and one ormore sweat analyzers, wherein the one or more sweat stimulators areinterspersed with the one or more sweat analyzers.
 5. The device ofclaim 1, wherein the sweat stimulator is configured to use a pair ofiontophoresis electrodes to drive a sweat stimulant into the firstregion.
 6. The device of claim 5, wherein a return electrode is locatedon a periphery of the device.
 7. The device of claim 5, wherein thesweat stimulant comprises a chemical stimulant that interacts stronglywith nicotinic receptors on a sweat gland.
 8. The device of claim 1,wherein the sweat stimulator is one of: electrically isolated from thesweat analyzer, or fluidically isolated from the sweat analyzer.
 9. Thedevice of claim 1, wherein the sweat analyzer further comprises acollector configured to collect and convey the sweat sample from thesecond region to the sweat analyzer.
 10. The device of claim 9, whereinthe collector further comprises a wicking material.
 11. The device ofclaim 1, wherein the first region is separated from the second region bya distance of 0.1 mm to 30 mm.
 12. The device of claim 1, furthercomprising a plurality of sweat stimulators and one or more sweatanalyzers, and wherein the plurality of sweat stimulators and the one ormore sweat analyzers are spatially arranged to increase the probabilityof a SAR sweating response underneath the one or more sweat analyzers.13. The device of claim 1, further comprising a plurality of sweatstimulators and a plurality of sweat analyzers, and wherein theplurality of sweat stimulators and the plurality of sweat analyzers arearranged spatially in a hexagonal pattern.
 14. The device of claim 12,wherein the plurality of sweat stimulators and the one or more sweatanalyzers are arranged in a concentric pattern.
 15. A wearable sweatsensing device, comprising: means for stimulating sweat in a firstregion of a device wearer's skin and for stimulating sudomotor axonreflex (SAR) sweat in a second region of the device wearer's skin, thefirst region separated from the second region by a separation distance;and means for collecting a SAR sweat sample from the second region andmeasuring one or more analytes in the sweat sample.
 16. The device ofclaim 15, wherein the means for stimulating sweat further comprisesiontophoretically delivering a sweat stimulant to the first region. 17.A method, comprising: placing a sweat stimulator on a surface of a firstregion of an individual's skin; placing a sweat analyzer on a surface ofa second region of the individual's skin, wherein the second region isseparated from the first region by a separation distance; and causingsweat glands in the first region to generate sweat, and causing sweatglands in the second region to generate sweat by sudomotor axon reflex(SAR) sweating; collecting a sweat sample from the second region; andusing the sweat analyzer to measure one or more analytes in the sweatsample.
 18. The method of claim 17, wherein the causing step furthercomprises using iontophoresis to deliver a sweat stimulant to the firstregion.
 19. The method of claim 17, wherein the collecting step furthercomprises using a collector to bring sweat from the second region to thesweat analyzer.
 20. The method of claim 17, wherein the separationdistance is in a range of 0.1 mm to 30 mm.
 21. The method of claim 17,further comprising the step of spatially separating a plurality of sweatstimulators and at least one sweat analyzer in a hexagonal array.